The Epstein-Berr virus infects most of us – but why do only some get very ill?

About 1 in 10 people carry genetic variants that make them particularly vulnerable to Epstein-Barr virus (EBV), a ubiquitous pathogen increasingly associated with diseases such as multiple sclerosis and lupus. This finding, from a study of more than 700,000 people, could help explain why EBV causes serious illness in some people while leaving most of us virtually unscathed.

“Almost everyone is exposed to EBV,” says Chris Wincup of King’s College London, who was not involved in the research. “How is it that everyone is exposed to the same virus and that virus causes autoimmunity, but the majority of people do not end up with an autoimmune disease? This study offers an answer, he says.

The Epstein-Barr virus was first described in 1964, after researchers found particles of it in a type of cancer called Burkitt lymphoma. We now know that more than 90 percent of people are infected with EBV at some point because almost everyone produces antibodies against the virus.

In the short term, EBV is the leading cause of infectious mononucleosis, also called mono or glandular fever, which usually goes away within a few weeks. In some cases, EBV appears to contribute to serious, long-term autoimmune diseases, in which the immune system attacks the rest of the body. A 2022 study, for example, provided strong evidence that it is the ultimate cause of multiple sclerosis, in which the protective sheaths around the nerves are damaged, leading to difficulty walking.

“Why do humans, at a population level, respond so differently to the same viral infection? » says Caleb Lareau of Memorial Sloan Kettering Cancer Center in New York.

To find out, Lareau and colleagues looked at health data on more than 735,000 people from the UK Biobank study and a US cohort called All of Us. Participants had their genomes sequenced – crucially using blood samples. “When EBV infects, it leaves a copy of itself in certain cells” in the blood, Lareau explains. This means that the human genomes present in the study samples contained copies of the EBV genome.

The researchers found that some people had significantly more EBV DNA than others: 47,452 of the study participants (9.7%) had more than 1.2 complete EBV genomes per 10,000 cells. This means that although most participants largely cleared the virus after infection, this group did not.

Next, the team tried to determine why these people were more vulnerable to EBV. “Were there certain differences in their genome that predisposed them to having higher levels of EBV? says Ryan Dhindsa, team member at Baylor College of Medicine in Houston, Texas. “We found that there were 22 different regions of the genome associated with higher levels of EBV,” he says. “Encouragingly, many of these genomic regions that emerged had previously been associated with different immune-mediated diseases.”

The strongest associations were for genes that encode the major histocompatibility complex, a set of immune proteins that play an important role in distinguishing the body from invading pathogens. “Some people had different variants in their major histocompatibility complex,” says Dhindsa. Further experiments suggested that these variants affected the body’s ability to detect EBV infection.

“This virus has an effect on our immune system, and it has a persistent and permanent effect on our immune system in some people,” says Ruth Dobson of Queen Mary University of London. When viral DNA persists, it can continue to gently nudge the immune system, eventually causing it to attack the body, she says.

Finally, genetic variants associated with high levels of EBV were also associated with many other traits and conditions – including a higher risk of autoimmune diseases such as rheumatoid arthritis and lupus, strengthening the evidence that the virus is involved in their origin.

The team also discovered an association between these variants and feeling unwell or tired. This was intriguing, because some studies suggest that EBV may be a causative factor in myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS). Because of the huge sample size, “we can say with certainty that this signal is there,” says Dhindsa. “But at this point we don’t know exactly what the relationship is.”

For Wincup, one of the main benefits of the results is the identification of exactly which parts of the immune system are disrupted by persistent EBV. These components could then be targeted with specific treatments, potentially reducing the harms of EBV-related conditions.

Another possibility is to vaccinate people against EBV. So far, only experimental vaccines have been developed. Vaccination against EBV would be a radical step, Wincup believes. “A lot of people think of EBV as a pretty benign disease,” he says. However, the conditions it is associated with take a heavy toll on a significant number of people. “So how benign is it?” »